Diabetes is a disorder of carbohydrate metabolism characterized by hyperglycemia and glucosuria resulting from insufficient production or utilization of insulin. Diabetes severely affects the quality of life of large parts of the populations in developed countries. Insufficient production of insulin is characterised as type 1 diabetes and insufficient utilization of insulin is type 2 diabetes.
Dyslipidemia, or abnormal levels of lipoproteins in serum, is a frequent occurrence among diabetics. In type 1 diabetes with optimal glycaemic control the concentrations of serum lipoproteins are typically characterized by normal to subnormal very low density lipoprotein (VLDL), elevated high density lipoprotein (HDL) cholesterol and normal to subnormal low density lipoprotein (LDL) cholesterol. Lipoprotein profile in type 1 diabetic patients with good glycaemic control is not atherogenic. In fact, it seems antiatherogenic although lack of lipoprotein abnormalities does not exclude the possibility that certain compositional alterations may be potentially atherogenic. In type 1 diabetics with poor glycaemic control the serum concentration of lipoproteins are typically characterized by increased VLDL, reduced HDL cholesterol and increased LDL cholesterol. This profile is atherogenic but it may be corrected by intensive insulin treatment of the patient to reach a state of good glycaemic control.
In type 2 diabetes abnormalities of serum lipids and lipoproteins are much more frequent than in type 1 diabetes. Dyslipidemia in type 2 diabetes is typically characterized by elevated serum and VLDL triglycerides, low HDL cholesterol, normal to elevated levels of LDL cholesterol and increased levels of small dense, LDL particles in the blood. Serum and VLDL triglycerides are usually 1.5-3 times higher in type 2 diabetics as compared to non-diabetic controls with matched body mass index, age and sex. Regardless of the mode of treatment of type 2 diabetes, the characteristic lipoprotein profile is atherogenic. Furthermore, the excessive postprandial lipaemia is positively correlated with fasting serum triglyceride levels in type 2 diabetics. Taken together these abnormalities are significant risk factors not only for coronary heart disease but also for the progression of coronary artery disease.
Dyslipidemia is one of the main contributors to the increased incidence of coronary events and deaths among diabetic subjects. Several epidemiological studies have confirmed this by showing a several-fold increase in coronary deaths among diabetic subjects when compared with non-diabetic subjects. Although the lipid profiles in type 1 diabetes and in type 2 diabetes both exhibit potentially atherogenic features, the lipoprotein profile in type 2 diabetes is atherogenic regardless of the mode of treatment. In type 2 diabetes the problem is of immense proportions since the majority of the patients have atherogenic dyslipidemia. In terms of atherogenic potential, dyslipidemia is comparable to hypercholesterolemia. Therefore, to relieve this burden accompanying diabetes new therapeutic approaches are needed.
Several drugs are being used in the treatment of dyslipidemia. The drugs can intervene by lowering cholesterol (LDL and total cholesterol) or by lowering triglyceride levels in plasma. Treatment of hyperlipidemia using statins or PPAR/LXR modulating compounds such as fibric acid derivatives have been used to lower serum levels of cholesterol and triglyceride. Statins such as atorvastatin, lovastatin, fluvastatin, simvastatin and pravastatin are HMG CoA reductase inhibitors which act by inhibiting cholesterol synthesis and upregulate LDL receptors in liver. Statins are used to treat elevated LDL, and common side effects are myositis, arthralgias, gastrointestinal upset and elevated liver function tests. The fibric acid derivatives e.g. clofibrate, gemfibrozil, fenofibrate and ciprofibrate, stimulate lipoprotein lipase that breaks down lipids in lipoproteins and may decrease VLDL synthesis. Fibric acid derivatives are used to treat elevated triglyceride levels and among the side effects are myositis, gastrointestinal upset, gallstones and elevated liver function tests. Other drug types used for treatment of hyperlipidemia are bile acid binding resins (bile acid sequestrants), e.g. cholestyramine and cholestipol, with the major indication being elevated LDL. Bile acid binding resins promote bile acid excretion and they increase LDL receptors in the liver. Common side effects are bloating, constipation and elevated triglycerides. Nicotinic acid decreases VLDL synthesis and is used for treatment of elevated LDL and VLDL. Among the side effects of nicotinic acid are cutaneous flushing, gastrointestinal upset, elevated glucose, uric acid and liver function tests. Thus, there is a need for the therapeutic benefits of several antidyslipidemic drugs while simultaneously reducing the severe side effects.
Human GLP-1 is a 37 amino acid residue peptide originating from preproglucagon which is synthesized i.a. in the L-cells in the distal ileum, in the pancreas and in the brain. GLP-1 is an important gut hormone with regulatory function in glucose metabolism and gastrointestinal secretion and metabolism. Processing of preproglucagon to give GLP-1(7-36)amide, GLP-1(7-37) and GLP-2 occurs mainly in the L-cells. A simple system is used to describe fragments and analogues of this peptide. Thus, for example, Gly8-GLP-1(7-37) designates a fragment of GLP-1 formally derived from GLP-1 by deleting the amino acid residues Nos. 1 to 6 and substituting the naturally occurring amino acid residue in position 8 (Ala) by Gly. Similarly, Lys34(Nε-tetradecanoyl)-GLP-1(7-37) designates GLP-1(7-37) wherein the ε-amino group of the Lys residue in position 34 has been tetradecanoylated. PCT publications WO 98/08871 and WO 99/43706 disclose derivatives of GLP-1 analogs, which have a lipophilic substituent. These stable derivatives of GLP-1 analogs have a protracted profile of action compared to the corresponding GLP-1 analogs. In addition to a number of other desirable effects, GLP-1 compounds have also been shown to lower plasma levels of triglycerides and cholesterol (WO 2001/66135).
A number of structural analogs of GLP-1 were isolated from the venom of the Gila monster lizards (Heloderma suspectum and Heloderma horridum). Exendin-4 is a 39 amino acid residue peptide isolated from the venom of Heloderma horridum, and this peptide shares 52% homology with GLP-1. Exendin-4 is a potent GLP-1 receptor agonist which has been shown to stimulate insulin release and ensuing lowering of the blood glucose level when injected into dogs. Exendin-4, exendin-4 analogs and derivatives of any of these as well as methods for production thereof can be found in WO 99/43708, WO 00/66629, and WO 01/04156. The group of GLP-1(1-37), exendin-4(1-39), analogs thereof and derivatives thereof, (hereinafter designated GLP-1 compounds) are potent insulinotropic agents.